7β-Hydroxy-3-heterocyclicthio-methyl cephalosporin intermediates

ABSTRACT

The compounds of this invention are 7β-hydroxy-3-heterocyclicthiomethyl cephalosporins useful as intermediates for the preparation of 7β-acyloxy cephalosporins.

This is a division of application Ser. No. 588,096 filed June 18, 1975,now U. S. Pat. No. 4,020,057.

This invention relates to a new series of cephalosporin compounds whichhave antibacterial activity and to intermediates for the preparationthereof. In particular, the biologically active cephalosporin compoundsof this invention are characterized by having an acyloxy group at the7β-position of the cehem nucleus. Also, this invention extends tomethods and compositions for treating certain bacterial infections usingthese new compounds.

The compounds of this invention are represented by the followingstructural formula ##STR1## in which: R¹ is an acyl group selected fromthe group consisting of: ##STR2## where: X is thienyl; dihydropheynl;phenyl; phenyl mono-substituded with hydroxy, hydroxymethyl, formamide,ureido, carboxymethylamino; 3-fluoro-4-hydroxyphenyl or3,4-dihydroxyphenyl;

A is NH₂, OH, COOH or SO₃ H; or formyloxy when X is phenyl;

Y is thienyl tetrazolyl, phenoxy, cyano, sydnone or aminomethylphenyl;

Z is methyl, trifluoromethyl, trifluroroethyl, cyanomethyl or pyridyl;

m is zero to two; and

R² is acetoxy or SHet where Het is a five or six membered heterocyclicring containing carbon and one to four atoms selected from the groupconsisting of N, O and S, each such ring being unsubstituted orsubstituted with from one to two groups selected from lower alkyl,alkoxyaikyl and trifluoromethyl, each alkyl or alkoxy group having fromone to four carbon atoms. or a non-toxic pharmaceutically acceptablesalt thereof.

It will be recognized that the 4-caroboxylic acid group of the compoundsof Formula 1 may be readily esterified by methods well known to the art.These esters include, for example, simple alkyl and aryl esters as wellas esters which are easily cleaved within the body to the parent acidsuch as indenyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl,glycyloxymethyl, phenyiglycyloxymethyl and thienylglycyloxymethyl estersand others, Of course, when A is COOH, this group may be similarlyesterified. All such esters are included within the scope of thisinvention.

Preferred compounds of this invention are represented by Formula I whereR² is acetoxy or SHet and Het is unsubstituted or methyl substituted1,2,3-triarolyl, 1,2,4-triazolyl, 1,2,3,4-tetrazolyl, oxazolyl,thiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl.

Advantageous compounds of this invention are represented by Formula Iwhere X is phenyl, A is NH₂ or OH, Y is thienyl or phenoxy, Z istrifluoromethyl, m is zero and R² is acetoxy.

Examples of the most preferred 7β-acyloxy substituents (R¹ O--) of thecompounds of Formula I are listed below:

a-hydroxyphenylacetoxy

a-aminophenylacetoxy

a-amino-4-hydroxyphenylacetoxy

trifluoromethylmercaptoacetoxy

methylmercaptoacetoxy

2,2,2-trifluoroethylsulfinylacetoxy

thienylacetoxy

tetrazolylacetoxy

cyanoacetoxy

phenoxyacetoxy

a-carboxythienylacetoxy

a-carboxyphenylacetoxy

a-sulfophenylacetoxy

methylsulfonylacetoxy

cyanomethylmercaptoacetoxy

a-amino-4-carobxymethylaminophenylacetoxy

a-amino-3-fluoro-4-hydroxyphenylacetoxy

3-sydnoneacetoxy

4-pyridylthioacetoxy

2-aminomethylphenylacetoxy.

Particularly preferred are the compounds7β-(D-α-aminophenylacetoxy)cephalosporanic acid,7β-phenoxyacetoxy-cephalosporanic acid,7β-trifluoromethylmercaptoacetoxy- cephalosporanic acid and7β-(D-α-hydroxyphenylacetoxy)-cephalosporanic acid.

Cephalosporins containing a 7α-hydroxy group with a methyl oracetoxymethyl substituent at the 3-position have been described bySheehan et al. [J. Org. Chem. 39:1444 (1974)]. Japanese Pat No. 9049982discloses 7-acyloxy(desacetoxy-cephalosporanic and -cephalosporanic)acidesters. Specifically described is the compound7c-phenoxyacetoxy-3-desacetoxycephalosporanic acid methyl ester. Noexamples of the 7β-hydroxy and 7β-acyloxy cephalosporins of thisinvention, however, are believed to be known to the art.

The compounds of Formula I are prepared by esterification of anappropriate 7β-hydroxy cephalosporin nucleus of Formula II: ##STR3## inwhich: R² is acetoxy or SHet where Het is a five or six memberedheterocyclic ring containing carbon and one to four atoms selected fromthe group consisting of N, O and S, each such ring being unsubstitutedor substituted with from one to two groups selected from lower alkyl,alkoxyalkyl and trichloromethyl, each alkyl or alkoxy group having fromone to four carbon atoms; and

R³ is hydrogen or an easily removable ester protecting group, by wellknown esterification methods, for example by reaction of a compound ofFormula II with an appropriate acid (R¹ OH) or other esterifying agent,preferably an acid chloride (R¹ Cl), followed by removal of theprotective groups when present.

The carboxylic acid group of the esterifying agent may be activated byany of the standard methods such as conversion to the mixed anhydride,acid imidazolide or activated ester. In addition, a reagent such asdicyclohexylcarbodiimide can be used provided that the carboxyl group onthe cephem nucleus is protected with an easily removable esterprotecting group.

The term "easily removable ester protecting group" is one which hasacquired a definite meaning within the cephalosporin and peptide art.Many such groups are known which are used to protect the carboxyl groupduring subsequent chemical reactions and are later removed by standardmethods to give the free carboxylic acid. Known ester protecting groupsinclude 2,2,2-trichloroethyl, C_(4-C) ₆ -tertiary alkyl, C₅ -C₇-tertiary alkenyl, C₅ 14 C₇ -tertiary alkynyl, C₁ 14 C₆ -alkanoylmethyl,N-phthalimidomethyl, benzoyl-methyl, halobenzoylmethyl,methylbenzoylmethyl, methane-sulfonylbenzoylmethyl, phenylbenzoylmethyl,benzyl, nitro-benzl, methoxybenzyl, benzyloxymethyl, nitrophenyl,methoxyphenyl, benzhydryl, trityl, trimethylsilyl, triethyl-silyl andthe like. The choice of an ester protecting group is well within theability of one skilled in the art. Factors which are considered includethe subsequent reaction conditions the group must withstand and theconditions desired for removing the protecting group. Because thenovelty of this invention lies within the new bicyclic nucleus, thechoice of a protecting group is not critical to the invention.

When A is NH₂, the α-amino group of the esterifying agent is,preferably, protected prior to esterification with an easily removableamine protecting group. The term "easily removable amine protectinggroup" is well known in the art and includes many groups commonly usedin the synthesis of cephalosporins and peptides. These include trityl,t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxy-carbonyl, themethyl acetoacetate adduct and the like. Divalent amine protectinggroups include phthaloyl, imines and similar groups. The choice of theprotecting group depends on various factors such as the subsequentchemical reaction conditions the group must withstand and the conditionsdesired for removing the protecting group and are within the ordinaryability of one skilled in the art. As with the ester protecting groups,the choice of the amine protecting group is not critical to thisinvention.

The compounds represented by Formula II above are also considered asobjects of this invention.

The compounds of Formula I where R² is SHet are also prepared bydisplacement of a 7β-acyloxy cephalosporanic acid with amercaptoheterocycle in an aqueous, slightly basic medium.

The protective groups can be removed according to methods well knows tothe art, such as with trifluoroacetic acid when t-butyl ort-butoxycarbonyl protective groups are used. The resulting salt isconverted to zwitterionic product or to the free acid by means of abasic ion exchange resin such as polystyrene-amine ion exchange resin(Amberlite IR-45) or else by basification of an aqueous solution of thesalt.

The esterifying agents used as starting materials are either known orprepared by known methods.

The 7β-hydroxy cephalosporin starting materials of Formula II areprepared by reduction of the corresponding 7-oxo cephalosporins ofFormula III: ##STR4## where R² is defined as above and R³ is an easilyremovable ester protecting group with, for example, a metal hydridereducing agent such as sodium borohydride according to standardprocedures.

The 7-oxo cephalosporins of Formula III are prepared by treatment of anester of the corresponding 7-amino cephalosporin with3,5-di-t-butyl-1,2-dioxobenzene, prepared by oxidation of3,5-di-t-butylcatechol with for example silver oxide, followed by acidhydrolysis of the product thus formed.

The compounds of this invention are capable of forming salts with, forexample, the alkali metals such as sodium or potassium, the alkalineearth metals such as calcium or with the ammonium cation. When A is NH₂,the compounds can exist as the zwitterion or as an acid or base salt.These salts are prepared by standard methods using a wide variety ofnon-toxic pharmaceutically acceptalbe acids and bases known in the artand are also considered as objects of this invention.

It will be recognized that due to the asymmetric α-carbon atom in the7β-acyloxy group of Formula I when ##STR5## optical isomers will exist.Racemic or resolved products are obtained depending upon whether aracemic or resolved side chain acid is used as an esterifying agent. Theresolved side chain acids are readily obtained from the racemiccompounds by resolution according to well known methods, includingfractional crystallization of a salt formed with an optically activeacid or base. All of the isomers, including separated isomers aremixtures thereof, are included within the scope of this invention.

The compounds of Formula I above are effective antibacterial agents andexhibit activity against, for example Staph.Aureus, Klebsiella andEnterobacter bacteria.

Pharmaceutical compositions having antibacterial activity which comprisea pharmaceutical carrier containing an active but non-toxic quantity ofa compound of Formula I as well as methods of combatting bacterialinfections by administering such a composition to an infected host in anontoxic amount sufficient to combat such infections are also objects ofthis invention. The administration may be orally or by parenteralinjection such as subcutaneously, intramuscularly or intravenously. Theinjection of suitably prepared sterile solutions or suspensionscontaining an effective, nontoxic amount of the new cephalosporincompound is the preferred route of administration.

The compounds of Formula I are formulated and administered in the samemanner as other cephalosporins. The dosage regimen comprisesadministration, preferably by injection, of an active but nontoxicquantity of a compound of Formula I. The precise dosages are dependentupon the age and weight of the subject and on the infection beingtreated and can be determined by those skilled in the art based on thedata disclosed herein compared with that available to the art attainedwith known cephalosporins.

The following examples illustrate the invention, ut are not to beconstrued as limiting the scope thereof. Temperatures are in degreesCentigrade unless otherwise stated.

EXAMPLE 1 7β-Hydroxycephalosporanic acid

To a solution of 5 g (22.5 mmol.) of 3,5-di-t-butylcatechol in 75 ml. ofether at 0° was added 25 g. of silver oxide. The reaction mixture wasstirrred at 0° for 30 minutes then at ambient temperature for anadditional 30 minutes. The mixture was filtered and the filtrate wasevaporated to dryness. Benzene was added to the residue and theresulting precipitate was collected by filtration and air dried to give3,5-di-t-butyl-1,2-dioxobenzene, m.p. 110-112°. 0

A solution of 3.28 g. (10 mmol. ) of 7l -amino-cephalosporanic acidt-butyl ester and 2.20 g. (10 mmol.) of 3,5-di-t-butyl-1,2-dioxobenzenein 50 ml. of tetrahydrofuran containing 5 g. of 5A molecular sieves wasmaintained at 4° for 12 hours. The mixture was filtered, 3 g. of oxalicacid and 10 ml. of water were added to the filtrate and the solution wasallowed to stand at 4° for 12 hours. The tetrahydrofuran was evaporatedand the aqueous residue was partitioned between 50 ml. of benzene and 50ml. of wter. The insoluble material was removed by filtration, thelayers were separated and the organic phase was diluted with hexane andextrated with water. Sodium chloride solution was added to the combinedaqueous phases, and they were extracted with ether. The ether extractwas dried and evaporated to near dryness. Addition of benzene and hexanecontaining water induced crystallization of 7-oxocephalosporanic acidt-butyl ester hydrate.

A solution of 1.38 g. (4mmol.) of 7-oxocephalosporanic acid t-butylester hydrate in 50 ml. of isopropanol and 3 ml. of water was cooled to0° (ice bath) and 0.150 g. (4 mmol.) of sodium borohydride was addedwith stirring. The reaction mixture was stirred for five minutes thendecomposed by addition of acetic acid. The mixture was extracted withethyl acetate and the organic phase was washed with water, dried (MgSO₄)and evaporated to dryness to give a residue which was recrystallizedfrom ethyl acetate-hexane to give 7β-hydroxycephalosporanic acid t-butylester.

    C.sub.14 H.sub.19 NO.sub.6 S. 0.25 H.sub.2 0

Calculated: 50.36% C; 5.89% H; 4.20% N.

Found: 50.64% C; 5.95% H; 4.02% N.

7β-Hydroxycephalosporanic acid t-butyl ester (1.0 g.) was stirred in 10ml. of trifluoroacetic acid containing 1. anisole at 25° for two hours.The reaction mixture was evaporated to dryness, the residue wastriturated with etherhexane and the precipitated product was collectedand recrystallized from tetrahydrofuran-hexane to give the titlecompound.

    C.sub.10 H.sub.11 NO.sub.6 S. 0.66 C.sub.4 H.sub.8 O. 0.5 H.sub.2 O

Calculated: 46.03% C; 5.29% H; 4.26% N.

Found: 46.38% C; 5.12% H; 3.90% N.

EXAMPLE 2 7β-(D-α-aminophenylacetoxy)cephalosporanic acid

To a solution of 0.126 g. (0.5 mmol.) ofD-N-t-butoxycarbonylphenylglycine in 10 ml. of tetrahydrofuran at -15°under a nitrogen atmosphere was added 0.075 ml. (0.5 mmol.) oftriethylamine followed by 0.03 ml. (0.5 mmol.) of ethyl chloroformate.The mixture was stirred for 15 minutes then a solution of 0.165 g. (0.5mmol.) of 7β-hydroxycephalosporanic acid t-butyl ester in 25 ml. oftetrahydrofuran was slowly added and the resulting mixture was stirredat 0° for one hour, then at ambient temperature for 12 hours. Water wasadded to the reaction mixture and it was extracted repeatedly withether. The combined extracts were washed with saturated sodium chloridesolution, dried and evaporated to dryness to give a residue which waschromatographed on silica with benzene-ethyl acetate as eluant to give7β-(D-α-N-t-butoxycarbonylaminophenylacetoxy)cephalosporanic acidt-butyl ester.

7β-(D-α-N-t-Butoxycarbonylaminophenylacetoxy)-cephalosporanic acidt-butyl ester (0.2 g.) was stirred with 20% trifluoroacetic acid inmethylene choride containing anisole at 25° % for three hours. Thesolution was evaporated to dryness and the residue was washed withhexane. Ether was added to the residue to give the title compound.

    C.sub.18 H.sub.18 N.sub.2 O.sub.7 S. 0.3 CF.sub.3 CO.sub.2 H

Calculated: 46.16% C; 3.68% H; 5.38% N.

Found: 50.81% C; 4.30% H; 6.35% N.

EXAMPLE 3 7β-Trifluoromethylmercaptoacetoxycephalosporanic acid

A solution of 0.40 g. (2.5 mmol.) of trifluoromethylmercaptoacetic acidand 0.35 g. (2.75 mmol.) of oxalyl chloride in 3 ml. of benzene wascooled to 0° and 0.20 g. of pyridine in 1 ml. of benzene was added underan argon atmosphere. The reaction mixture was stirred for 15 minutesthen filtered. The filtrate was added dropwise to a stirred solution of0.66 g. (2.0 mmol.) of 7β-hydroxy-cephalosporanic acid t-butyl ester in80 ml. of ether containing 0.15 ml. of pyridine at 0°. After addition,the mixture was stirred at 25° for 0.5 hour then ice water was added andthe layers were separated. The aqueous phase was thoroughly extractedwith ether, and the combined organic phases were washed with saturatedsodium chloride solution, dried and evaporated to dryness to give aresidue which was chromatographed on silica with benzene-ethyl acetate,as eluent to give 7β-trifluoromethylmercaptoacatoxycephalcsporanic acidt-butyl ester. 7β-Trifluoromethylmercaptoacetoxycephalosporanic acidt-butyl ester (0.4 g.) was stirred in 10 ml. of trifluoroacetic acid at25° for three hours. The solution was evaporated to dryness to give thetitle compound.

    C.sub.13 H.sub.12 F.sub.3 NO.sub.7 S.sub.2

Calculated: 37.59% C; 3.06% H; 3.37% N.

Found: 37.67% C; 3.06% H; 3.00% N.

EXAMPLE 4

7β-Phenoxyacetoxycephalosporanic acid

To a solution of 0.448 g. (1.35 mmol.) of 7βhydroxycephalosporanic acidt-butyl ester and 0.1 ml. of pyridine in 60 ml. of anhydrous ether at 0°was added 0.24 g. (1.4 mmol.) of phenoxyacetylchloride. The reactionmixture was stirred for one hour in the cold then for 30 minutes atambient temperature. Cold water was added to the mixture, the layerswere separated and the aqueous phase was extracted repeatedly withether. The combined ether layers were washed with saturated sodiumchloride solution, dried (Na₂ SO₄) and evaporated to dryness. Theresidue was chromatographed on silica with benzene-ethyl acetate aseluant to give 7β-phenoxyacetoxycephalosporanic acid t-butyl ester.

    C.sub.22 H.sub.25 NO.sub.8 S

Calculated: 57.01% C; 5.44% H; 3.02% N.

Found: 57.48% C; 5.54% H; 2.60% N.

7β-Phenoxyacetoxycephalosporanic acid t-butyl ester was treated withtrifluoroacetic acid as previously described to give the title compound.

    C.sub.18 H.sub.17 NO.sub.8 S

Calculated: 53.07% C; 4.21% H; 3.44% N.

Found: 53.12% C; 4.30% H; 3.24% N.

EXAMPLE 5

7β(D-α-Hydroxyphenylacetoxy)cephalosporanic acid

To a solution of 0.659 g. (2.0 mmol.) of 7β-hydroxycephalosporanic acidt-butyl ester in 60 ml. of methylene chloride containing 0.16 ml. ofpyridine at 0° under a nitrogen atmosphere was added 0.600 g. (2.2mmol.) of D-O-dichloroacetylmandeloyl) chloride in 10 ml. of methylenechloride. The reaction mixture was stirred for 30 minutes in the cold,then warmed to ambient temperature. The aqueous phase was thoroughlyextracted with methylene chloride. The organic layers were combined,washed with saturated sodium chloride, dried (Na₂ SO₄) and evaporated todryness to give a residue which was chromatographed on silica withbenzeneethyl acetate as eluant to give7β-(D-α-dichloroacetoxyphenylacetoxy) cephalosporanic acid t-butylester.

7β-(D-α-Dichloroacetoxyphenylacetoxy)cephalosporanic acid t-butyl ester(0.60 g.) was stirred with 50 ml. of 20% trifluoroacetic acid inmethylene chloride containing anisole at 25° for two hours. The solutionwas evaporated to dryness and the residue was washed with hexane andchromatographed on silica with 1% acetic acid in benzeneethyl acetate aseluant, give 7β-(D-α-dichloroacetoxyphenylacetoxy)cephalosporanic acid.

7β-(D-α-Dichloroacetoxyphenylacetoxy)cephalosporanic acid (0.330 g.) wasdissolved in acetone and a solution of 3:1 0.1 M Na₂ HPO₄ :0.1 M NaH₂PO₄ buffer was added dropwise until pH 7.2. The solution was allowed tostand for 20 minutes then it was cooled and acidified with dilutephosphoric acid until pH 1.5. The acidic solution was extracted withether and the extract was washed with saturated sodium chloridesolution, dried (MgSO₄) and evaporated to dryness. The residue wascrystallized from ethyl acetate-hexane to give the title compound.

EXAMPLE 6

When 7β-hydroxycephalosporanic acid t-butyl ester is esterified(acylated) with other esterifying (acylating) agents known to the art,particularly with an acid or activated form of an acid listed below,suitably protected as necessary

α-amino-4-hydroxyphenylacetic acid

methylmercaptoacetic acid

2,2,2-trifluoroethylsulfinylacetic acid

2-thienylacetic acid

1-tetrazolylacetic acid

cyanoacetic acid

α-carboxy-2-thienylacetic acid

α-carboxyphenylacetic acid

α-sulfophenylacetic acid

methylsulfonylacetic acid

cyanomethylmercaptoacetic acid

α-amino-4-carboxymethylaminophenylacetic acid

α-amino-3-fluoro-4-hydroxyphenylacetic acid

3-sydnoneactic acid

4-pyridylthioacetic acid

2-aminomethylphenylacetic acid according to the procedures described inExamples 2, 3, 4 or 5 followed by removal of the protective groups whennecessary as described therein, the corresponding7β-acyloxycephalosporanic acids are prepared.

EXAMPLE 7

When the t-butyl ester of a 7-amino-3-heterocycliothiomethylcephalosporin listed below:

7-amino-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid7-amino-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid 7-amino-3(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid7-amino-3-(5-n-butyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(1,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(3-methyl-1,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(3-ethyl-1,2,4-thiadiazol-5-ylthiomethyl-3-cephem-4-carboxylicacid

7-amino-3-(thiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2-methylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(4-methylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2,4-dimethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(2-ethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(4-ethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2,4-diethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(5-methyl-1,3,4-oxadiazol-2-ylthiomethyl-3-cephem-4-carboxylicacid

7-amino-3-(oxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2-methyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(4-methyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2,4-dimethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2-ethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(4-ethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2,4-diethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(tetrazol-5-ylthiomethyl)-3-cephem-carboxylic acid

7-amino-3-(1-ethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(1,2,4-triazol-3-ylthiomethyl)3-cephem-4-carboxylic acid

7-amino-3-(5-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(1-methyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(1,5-dimethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(4,5-dimethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(4-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(5-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(1-ethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(4,5-diethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(1,3-diethyl-1,2,4-triazol-5-yltheomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(4-methoxymethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(4-methyl-5-trifluoromethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(3-methyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(5-methyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(3,5-dimethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(3-ethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(5-ethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(3,5-diethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(3-methyoxymethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7-amino-3-(4-pyridylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(3-pyridylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(4-pyrimidylthiomethyl)-3-cephem-4-carboxylic acid

7-amino-3-(2-pyrazinylthiomethyl)-3-cephem-4-carboxylic acid

is substituted in the procedure of Example 1 for 7-aminocephalosporanicacid t-butyl ester, the resulting7-oxo-3-heterocycliothiomethyl-3-cephem-4-carboxylic acid t-butyl esteris reduced with sodium borohydride as described therein and the reducedproduct is treated with trifluoroacetic acid as described above toremove the t-butyl ester, the following7β-hydroxy-3-heterocyliothiomethyl-3-cephem-4-carboxylic acids areobtained:

7β-hydroxy-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(4-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(5-ethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(5-n-butyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(3-methyl-1,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(3-ethyl-1,2,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(2-methylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(4-methylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(2,4-dimethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(2-ethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(4-ethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(2,4-diethylthiazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(5-methyl-1,3,4-oxadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(2-methyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(4-methyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(2,4-dimethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(2-ethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(4-ethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(2,4-diethyloxazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(1-ethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(5-methyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1-methyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1,5-dimethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(4,5-dimethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(4-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(5-ethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1-ethyl-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(4,5-diethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1,3-diethyl-1,2,4-triazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(4-methoxymethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(4-methyl-5-trifluoromethyl-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(3-methyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(5-methyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(3,5-dimethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(3-ethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(5-ethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(3,5-diethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(3-methoxymethyl-1,2,3-triazol-4-ylthiomethyl)-3-cephem-4-carboxylicacid

7β-hydroxy-3-(4-pyridylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(3-pyridylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(4-pyrimidylthiomethyl)-3-cephem-4-carboxylic acid

7β-hydroxy-3-(2-pyrazinylthiomethyl)-3-cephem-4-carboxylic acid

EXAMPLE 8

When a 7β-hydroxy-3-heterocyclothiomethyl-3-cephem-4-carboxylic acidt-butyl ester prepared in Example 7 is esterified with an esterifyingagent known to the art particularly with an acid form of an acid listedbelow, suitably protected as necessary:

α-hydroxyphenylacetic acid

α-aminophenylacetic acid

α-amino-4-hydroxyphenylacetic acid

trifluoromethylmercaptoacetic acid

methylmercaptoacetic acid

2,2,2-trifluoroethylsulfinylacetic acid

2-thienylacetic acid

1-tetrazolylacetic acid

phenoxyacetic acid

α-carboxy-2-thienylacetic acid

α-carboxyphenylacetic acid

α-sulfophenylacetic acid

methylsulfonylacetic acid

cyanomethylmercaptoacetic acid

α-amino-4-carboxymethylaminophenylacetic acid

α-amino-3-fluoro-4-hydroxyphenylacetic acid

3-sydnoneacetic acid

4-pyridylthioacetic acid

2-aminomethylphenylacetic acid

according to the procedures of Examples 2, 3, 4 or 5 with removal of theprotective groups where appropriate as described therein, thecorresponding 7β-acyloxy-3-heterocyclicthiomethyl-3-cephem-4-carboxylicacids are prepared.

EXAMPLE 9

The sodium salt of 7β-trifluoromethylmercaptoacetoxycephalosporanic acidis prepared by dissolving the acid in ethyl acetate, adding a sodium2-ethylhexanoate solution and then slowly adding ether until the sodiumsalt is precipitated.

Sodium salts of the cephalosporins disclosed above may be similarlyprepared.

The sodium salt of 7β-trifluoromethylmercaptoacetoxycephalosporanic acidis converted to the free acid by treating an aqueous solution of thesalt with Amberlite IR-120H ion exchange resin.

EXAMPLE 10

An injectable pharmaceutical composition is prepared by dissolving100-150 mg. of 7β-trifluoromethylmercaptoacetoxycephalosporanic acidsodium salt in sterile water or sterile normal saline solution (1-2 ml.)

All other cephalosporin compounds within this invention are formulatedin a similar manner.

I claim:
 1. A compound of the formula: ##STR6## in which: R² is SHetwhere Het is selected from the group consisting of 1,2,3-triazolyl,1,2,4-triazolyl, tetrazolyl, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl,1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl andpyrazinyl, each such ring being attached to S through a carbon ringmember, each such ring being unsubstituted or substituted with from oneto two groups selected from lower alkyl, alkoxyalkyl andtrifluoromethyl, each alkyl or alkoxy group having from one to fourcarbon atoms; andR³ is hydrogen or an easily removable ester protectinggroup, or a non-toxic pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 in which R³ is hydrogen, benzhydryl,t-butyl, 2,2,2-trichloroethyl, benzyl, benzyloxymethyl, p-nitrophenyl,p-methoxyphenyl, p-nitrobenzyl or p-methoxybenzyl.
 3. A compoundaccording to claim 2 in which Het is unsubstituted or methyl substituted1,2,3-triazolyl, 1,2,4triazolyl, 1,2,3,4-tetrazolyl, oxazolyl,thiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl or 1,2,4-thiadiazolyl.4. A compound according to claim 3, said compound being7β-hydroxy-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid.
 5. A compound according to claim 3, said compound being7β-hydroxy-3-(1-methyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylicacid t-butyl ester.
 6. A compound according to claim 3, said compoundbeing7β-hydroxy-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid.
 7. A compound according to claim 3, said compound being7β-hydroxy-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylicacid t-butyl ester.